Adeno-Associated Virus Gene Therapy for Hemophilia

Abstract

In vivo gene therapy is rapidly emerging as a new therapeutic paradigm for monogenic disorders. For almost three decades, hemophilia A (HA) and hemophilia B (HB) have served as model disorders for the development of gene therapy. This effort is soon to bear fruit with completed pivotal adeno-associated viral (AAV) vector gene addition trials reporting encouraging results and regulatory approval widely anticipated in the near future for the current generation of HA and HB AAV vectors. Here we review the clinical development of AAV gene therapy for HA and HB and examine outstanding questions that have recently emerged from AAV clinical trials for hemophilia and other monogenic disorders.

Keywords: AAV; factor IX; factor VIII; gene therapy; hemophilia A; hemophilia B.

Figure 1

Annualized bleeding rate (ABR) for participants in (a) hemophilia A and (b) hemophilia B AAV gene therapy clinical trials before and after AAV vector administration. Data were extracted as follows: BMN270 (valoctocogene roxaparvovec) represents mean ABR (n = 134 participants) (58); SPK-8011 represents mean ABR of participants who maintained expression outside an AAV capsid immune response and were followed >1 year (n = 15) (56); SB-525 (giroctocogene fitelparvovec) represents mean ABR for participants following vector administration only (n = 4) (60); AAV-wt-FIX (scAAV2/8-LP1-hFIXco) represents median reported ABR (n = 10 participants) (22, 23); AMT-060 represents mean ABR (n = 10 participants) (25); AMT-061 (etranacogene dezaparvovec) represents mean ABR of all bleeding events (n = 54 participants) (103); SPK-9001 (fidanacogene elaparvovec) represents mean ABR (n = 10 participants) (27).

Figure 2

Relationship between annualized bleeding rate (ABR) and factor VIII (FVIII) activity. (a) The ABR and FVIII activity for all gene therapy recipients of 0.5–2 × 10¹² vg/kg of SPK-8011 (black squares), 4–6 × 10¹³ vg/kg AAV5-FVIII phase I/II (red circles), and 6 × 10¹³ vg/kg AAV5-FVIII phase III (blue triangles). Plotted FVIII activity levels are determined by one-stage assay or converted from a chromogenic assay results using a correction factor of 1.6 (56, 58, 61, 104). The black vertical line represents 10% of normal FVIII level. The blue shaded box represents recipients with an ABR ≤1. (b) Percentage of gene therapy recipients with an ABR ≤1 as a function of their FVIII activity determined by one-state assay. Ascending ABR data from gene therapy recipients were binned into groups of 10 and then plotted as a function of the maximum FVIII level in the binned group.

Figure 3

Multiyear factor VIII (FVIII) activity after AAV gene therapy. Data were extracted from publicly available publications or abstracts (56-58, 86-88). Points represent median FVIII levels (except for SB-525, where only mean values were available), and error bars are the interquartile range. Data are from cohorts that received AAV vectors doses of 3 × 10¹³, 6 × 10¹³, and 0.5–2 × 10¹² vg/kg of SB-525, AAV5-FVIII, and SPK-8011, respectively. Two of the participants who received SPK-8011 lost all FVIII expression due to a capsid cellular immune response within 3 months post vector administration and are not included. Plotted SPK-8011 participant data represent n = 15 at year 1, n = 11 at year 2, and n = 5 at year 3, reflecting duration of available follow-up data. FVIII activity was determined by one-stage assay or converted from a chromogenic assay result using a correction factor of 1.6 (56, 61, 104) for AAV5-FVIII results.